Nondisjunction Events in Humans
Overview Nondisjunction is the term that refers to when homologous chromosomes or sister chromatids fail to correctly separate during the process of cell division (1). This event leads to daughter cells that contain an abnormal number of chromosomes: an aneuploidy. This can happen in all organisms that have dividing cells with varing levels of viability. In humans the majority of aneuploidys are not compatible with life and result in a large percentage of miscariages. However there are a few specific nondisjunction events that are viable in humans and result in distinctive phenotypes. Meiosis 1 Nondisjunction: In this type of nondisjunction event homologous chromosomes fail to separate in anaphase 1 of the first meiosis cycle. Therefore instead of each daughter cell containing 1 of each of the homologs, one of the two daughter cells contains both of the identical homolog chromosomes while the other does not contain either. When meiosis 2 is completed this again results in 2 daughter cells with double the amount of genetic material from the original homologous chromosomes that failed to separate and 2 other daughter cells that lack the genetic material of that chromosome entirely. Once fertilized by sperm this results in two daughter cells that result in trisomies (contain an extra duplicate chromosome) and two daughter cells that result monosomies (lack 1 copy of the chromosome that failed to separate). Meiosis 1 is responsible for the majority of human aneuploidy disorders since 0% of the daughter cells result in euploid (normal) set of chromosomes (2). Meiosis 2 Nondisjunction: In this type of nondisjunction event sister chromatids fail to separate at anaphase 2 of the second meiosis cycle. Assuming the first meiosis cycle resulted in the correct division of chromosomes, and the nondisjunction event happened in only 1 of the resulting daughter cells from meiosis 1, 50% of the fertilized eggs remain chromosomally normal in number. However for the daughter cell where the chromatids failed to separate, the result is 1 trisomic daughter cell and 1 monosomic daughter cell once fertilized by the sperm. Viable Human Disorders Resulting from Meitotic Nondisjunction (without mosiacism) As mentioned before the majority of trisomies and monosomies resulting from nondisjunction in humans are not compatible with life and are normally lost as miscarriages within the first trimester of a pregnancy (2). In the majority of these viable cases, life can exist because the chromosome that is in excess or lacking does not contain genes are are essential for life or do not contain that many genes at all in comparison with other chromosomes. However this being stated, many of these viable cases do result in mild-severe physical and mental abnormalities. 'Monosomies:' Turner's Syndrome(X): Turner's Syndrome is the only viable monosomy in humans and is characterized by lack of a second X chromosome (1). These people are phenotypically and genetically considered females but commonly display some phenotypical abnormalities. Some of these include short stature, loss of ovarian function leading to infertility, and do not normally go through typical female puberty or develop secondary female sex characteristics unless supplemented with regular hormones (3). Other semi-common characteristics include kidney problems, heart defects, low hairlines, edema of the hands and feet, and skeletal abnormalities (3). Trisomies: Klinefelters Syndrome(XXY): Klinefelter's Syndrome is genetically classified as containing an extra X chromosome along with a normal X Y chromosomal pair. These people are male genetically and phenotypically but display many distinct characteristics. These males typically have smaller and nonfunctional primary and secondary sex characteristics including smaller testes, penis and less testosterone release therefore leading to infertility (3). Other common features include the possibility of breast enlargement and decreased facial and body hair. Cognitive disabilities such as delayed speech and learning development, unassertiveness, quietness, and sensitivity are also commonly associated with Klinefelter's (3). 47,XYY / Trisomy X(XXX): People with 47, XYY are male and genetically classified as containing an exta Y chromosome whereas in people with Trisomy XXX are female and contain an extra third copy of the X chromosome present in their genomes. People born with an extra Y or extra X are phenotypically normal although they may be taller than average and can also typically reproduce (3). There are some cognitive disabilities sometimes associated with XYY and Trisomy X including delayed speech, learning, and motor development as well as behavioral and emotional problems (3). Trisomy 21: Triosomy 21, otherwise commonly known as Down Syndrome, is genetically classified as containing 1 extra copy of the autosomal chromosome 21. People with this disorder display a variety of distinct facial feature s, weak muscle tone, delayed cognition development, and mild to moderate intellectual disabilities (3). People with Down Syndrome are also at risk for more serious medical conditions including vision and hearing problems, acid reflux, and hypothyroidism. There is a direct correlation between women over 35 having an increased risk for having a nondisjunction event leading to Trisomy 21 as well (3). Trisomy 18: Trisomy 18, otherwise known as Edward's Syndrome, is characterized genetically by the presence of an extra copy of the autosomal chromosome 18. Children born with this chromosomal defect typically do not live past 1 year old due to a variety of extreme medical problems resulting from abnormalities with many vital organs and heart defects (3). Some other characteristics associated with Edward's Syndrome include low birth weight, a small abnormally shaped head, mouth, and jaw, clenched fists with overlapping fingers and severe intellectual disabilities (3). This disorder is also positively correlated with increasing maternal age. 'Trisomy 13: '''Trisomy 13, otherwise known as Patau Syndrome, is characterized genetically by the presence of an extra copy of the autosomal chromosome 13. Infants born with this genetic abnormality do not normally survive past the first few weeks of live due to physical deformaties as well as severe intellectual disabilities (3). Some of these complications include spinal cord and brain abnormalities, underdeveloped eyes, a cleft lip, heart defects, extra extremities, and weak muscle tone (3). This disorder is also positively correlated with increasing maternal age as well. Mitotic Nondisjunction In mitotic nondisjunction, the somatic cell undergoes duplication and the sister chromatids fail to separate during anaphase. While this still results in the original cell or the new daughter cell containing either both of neither of the 2 chromatids resulting in aneuploidies, only cells that replicate from these cells will have chromosomal abnormalities. This results in mosaicism, or in other words, some of the somatic cells have aneuploidies while the rest of the replicating cells remain normal and euploid (4). However this does leave room for other complications to arise more readily such as some forms of cancer including retinoblastoma, or possible inactivation of enyzmes such as topoisomerase II, condensin, and separase (1). References 1."Nondisjunction." ''Wikipedia. Wikimedia Foundation, 12 June 2014. 2. Griffiths, Anthony JF. "Aneuploidy." An Introduction to Genetic Analysis. 7th ed. New York: W. H. Freeman, 2000., NCBI Bookshelf 3. "Conditions." Genetics Home Reference. U.S. National Library of Medicine, Jan. 2012. 4. Taylor, T. H. "The Origin, Mechanisms, Incidence and Clinical Consequences of Chromosomal Mosaicism in Humans." National Center for Biotechnology Information. U.S. National Library of Medicine, July-Aug. 2014. PubMed ID: 24667481